The present invention relates a process for making cyclopropane esters useful in the synthesis of pyrethroids which are useful as pesticides, and to intermediates useful in said process.
Esters of cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid with for example 3-phenoxybenzyl alcohol, xcex1-cyano-3-phenoxybenzyl alcohol and 2-methyl-3-phenylbenzyl alcohol are important insecticidal and acaricidal products, and esters of this acid are important intermediates in the manufacture of such products. These products are all chiral and it is preferred to manufacture such products as single enantiomers or in enantiomerically enriched form.
An asymmetric synthesis of single enantiomers of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one involving a trans- to cis-isomerisation step from a hydroxyester precursor is described in Tet. Lett., 1983, 24, 103. The conversion of the resulting 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one to deltamethrin is also described.
The use of L-proline as a chiral auxiliary for the asymmetric synthesis of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (I) from methyl 4,5-epoxy-3,3-dimethylpentanoate to give a mixture of cis- and trans-cyclopropyl isomers is described in Heterocycles, 1985, 23, 2859. This methodology does not enable the geometry of the cyclopropyl ring to be controlled. This reference also describes rearrangement of epoxyester (IIIa) to lactone (I) and trans-hydroxyester (VIa) but, under the reaction conditions, (VIa) cannot be rearranged to form (I), viz: 
Thus, it is desirable to prepare cis-pyrethroid acids (see, for example, pyrethroid acids of formula (V) in Scheme 1) using a process under which any trans-isomer formed will be rearranged to the cis-form.
The present invention provides a process for the preparation of cis-6,6-dimethyl-3-oxa-bicyclo[3.1.0]hexan-2-one which comprises either:
a) reacting a sulphonic ester of xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone with a compound of formula M(C1-6 alkoxide)y, in a suitable solvent; or
b) reacting a C1-4 alkyl ester of 4,5-epoxy-3,3-dimethylpentanoic acid with M(C1-6 alkoxide)y, in a suitable solvent;
wherein M is a suitable cation and y fulfills valency requirements.
It is preferred that the C1-6 alkoxide is an alkoxide that can function both as a base and a nucleophile, such as tert-butoxide.
It is preferred that M is an alkali metal salt (especially sodium or potassium), an alkaline earth metal (especially calcium or magnesium) or an organic cation (especially a quaternary ammonium such as NH4 or N(CH3)4). It is especially preferred that M is sodium or potassium.
Alkyl esters of 4,5-epoxy-3,3-dimethylpentanoic acid are preferably the methyl or ethyl esters of that acid.
Sulphonic esters of xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone include C1-4 alkylsulphonyl and phenylsulphonyl (wherein phenyl is optionally substituted with C1-4 alkyl) esters, such as the mesyl and tosyl esters.
In one aspect the present invention provides a process for the preparation of cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one which comprises either:
a) forming a sulphonic ester of xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone; and,
b) reacting the sulphonic ester with a compound of formula M(C1-6 alkoxide)y, in a suitable solvent; or
reacting a C1-4 alkyl ester of 4,5-epoxy-3,3-dimethylpentanoic acid with M(C1-4 alkoxide)y, in a suitable solvent;
wherein M is a suitable cation and y fulfills valency requirements.
Sulphonic esters of xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone can be formed, for example, by adaptation of literature methods or by reacting an appropriate hydroxymethyl lactone with a suitable sulphonyl chloride in the presence of a suitable base or mixture of bases (such as a tri(C1-4 alkyl)amine or a di(C1-4 alkyl)aminopyridine) in a suitable solvent.
In yet another aspect the present invention provides a sulphonic ester of xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone.
One of the advantages of the present invention is that any entiomeric excess present in xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone is preserved and, thus, the process of the present invention also allows the preparation of enantiomerically enriched cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one which, in turn, can be used to prepare enantiomerically enriched pyrethroid acids.
Thus, in another aspect the present invention provides a process for the preparation of enantiomerically enriched cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one which comprises:
a) forming enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone;
b) forming a sulphonic ester of the enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone; and,
c) reacting the sulphonic ester with a compound of formula M(C1-6 alkoxide)y, in a suitable solvent;
wherein M is a suitable cation and y fulfills valency requirements.
In a further aspect the present invention provides a process for the preparation of enantiomerically enriched cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one which comprises:
a) performing a Sharpless asymmetric dihydroxylation on a C1-4 alkyl ester of 3,3-dimethyl-4-pentenoate to form enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone;
b) forming a sulphonic ester of the enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone; and,
c) reacting the sulphonic ester with a compound of formula M(C1-6 alkoxide)y, in a suitable solvent;
wherein M is a suitable cation and y fulfills valency requirements.
6,6-Dimethyl-3-oxabicyclo[3.1.0]hexan-2-one produced according to the present invention is preferably enantiomerically enriched and has an enantiomeric excess greater than 90%, preferably greater than 98%.
The term xe2x80x9cenantiomeric excessxe2x80x9d is defined as:
(% major enantiomer)xe2x88x92(% minor enantiomer)
(% major enantiomer)+(% minor enantiomer)
Enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone can be prepared by Sharpless asymninetric dihydroxylation of a C1-4 alkyl ester of 3,3-dimethyl-4-pentenoate (see, for example, H C Kolb, M S Vannieuwenhze and K B Sharpless, Chemical Reviews, (1994) 94(8) 2483-2547, or H Becker and K B Sharpless, Angew. Chem. Int. Ed. Eng. (1996) 35 448-451); or by bioresolution (see, for example S M Robert, K Wiggins and G Casy (eds.) xe2x80x9cPreparative Biotransfornationsxe2x80x94Whole cells and isolated enzymes in organic synthesisxe2x80x9d John Wiley and Sons, (1993)).
In a further aspect the present invention provides a process for the preparation of a compound of formula (VI): 
in enantiomerically enriched form, wherein X and Y are, independently, halogen, C1-3 alkyl or C1-3 haloalkyl, which comprises:
a) forming enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone (such as by Sharpless asymmetric dihydroxylation or bioresolution);
b) forming a sulphonic ester of the enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone;
c) reacting the sulphonic ester with a compound of formula M(C1-4 alkoxide)y, in a suitable solvent to form enantiomerically enriched 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one;
d) reducing the enantiomerically enriched 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one under suitable conditions (such as using DIBAL in the presence of a solvent at low temperature) to provide a compound of formula (VII) in enantiomerically enriched form; and,
e) ring opening said compound of formula (VII) (such as by adaptation of methodologies described in S Takano, M Tanaka, K Seo, M Hirama and K Ogasawara, J. Org. Chem. (1985) 50 931-936 or J Tessier Chem Ind (1984) 199 which describe the conversion of a lactol to a dimethylvinyl cyclopropane derivative);
wherein M is a suitable cation and y fulfills valency requirements.
Halogen includes fluorine, chlorine or bromine.
C1-3 Alkyl and C1-3 haloalkyl groups include methyl and trifluoromethyl.
In a still further aspect the present invention provides a process for the preparation of a compound of formula (V): 
in enantiomerically enriched form, wherein X and Y are, independently, halogen, C1-3 alkyl or C1-3 haloalkyl, which comprises:
a) forming enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone (such as by Sharpless asymmetric dihydroxylation or bioresolution);
b) forming a sulphonic ester of the enantiomerically enriched xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone;
c) reacting the sulphonic ester with a compound of formula M(C1-6 alkoxide)y, in a suitable solvent to form enantiomerically enriched 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one;
d) reducing the enantiomerically enriched 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one under suitable conditions to provide a compound of formula (VII) in enantiomerically enriched form;
e) ring opening said compound of formula (VII) to provide a compound of formula (VI) in enantiomerically enriched form; and,
f) oxidising said compound of formula (VI) under suitable conditions (such as adoption or adaptation of the conditions described in G Green, W P Griffith, D M Hollinshead, S V Ley, and M Schroeder J. Chem. Soc. Perkin Trans. 1 (1984) 681-686; N G Bhat, B M Mane, G H Kulkarni and R B Mitra Indian J. Chem. Sect. B (1981) 204-206; or R S Dhillon, V K Gautam, S Singh and J Singh Indian J. Chem. Sect. B (1991) 574-578);
wherein M is a suitable cation and y fulfills valency requirements.
It is preferred that the process of the invention is conducted without isolating the sulphonic ester of xcex2,xcex2-dimethyl-xcex3-(hydroxymethyl)-xcex3-butyrolactone.
The process of the present invention, together with synthesis of the relevant starting materials, is illustrated in Scheme 1 below, wherein R is C1-4 alkyl and Rxe2x80x2 is the residue of a sulphonic acid (such as a C1-4 alkylsulphonic acid or a phenylsulphonic acid (wherein phenyl is optionally substituted with C1-4 alkyl), such as methanesulphonic acid or p-toluenesulphonic acid).
Although the compounds of formulae (I), (V), (VI) and (VII) are represented in Scheme 1 in enantiomeric forms, the invention is not limited to these forms, but covers all possible enantiomeric forms of these compounds. 
As shown in Scheme 1, lactone of formula (I) may be converted into pyrethroid acids (V) via a process involving reduction to the corresponding lactol (for example using diisobutylaluminium hydride (DIBAL)) followed by opening of the resulting lactol (for example using a Wittig reaction as described in J. Org. Chem., 1985, 50(7), 931-936) and finally oxidising the product so formed to the corresponding pyrethroid acid (for example as described in Indian J. Chem. Sect. B, 1991, 30(6), 574-578).
Examples of compounds of formula (V) include compounds having purely cis-cyclopropyl ring geometry, in racemic mixture, enantiomerically enriched or single enantiomer form, of various pyrethroid acids such as the compounds wherein: Xxe2x95x90Y=bromine (deltamethrin acid), Xxe2x95x90Y=methyl (chrysanthemic acid), X=chlorine and Y=methyl (permethrin acid) or X=chlorine and Y=trifluoromethyl (cyhalothrin acid).
Typically compound (I) can be made by reacting a compound of formula (IIa) or (III) with a suitable alkoxide (such as potassium tert-butoxide) in a suitable solvent (preferably an ether (such as tetrahydrofuran) or a polar solvent (such as N,N-dimethylformamide)) at an elevated temperature (such as in the range 10-100xc2x0 C.).
A compound of formula (IIa) can be prepared by reacting a compound of formula (II) with a suitable sulphonic acid chloride (such as mesyl chloride or tosyl chloride) in the presence of a suitable base (such as triethylamine) in a suitable inert solvent (such as dichloromethane) preferably at ambient temperature.
A compound of formula (III) can be prepared by oxidising a compound of formula (IV) with a suitable oxidising agent (such as a peroxy acid (for example m-chloroperoxybenzoic acid)) at ambient temperature in an inert solvent (such as dichloromethane).
The invention is illustrated by, but not limited to, the following Examples.